Individual differences in recovery from traumatic fear

Abstract

Although exposure to major psychological trauma is unfortunately common, risk for related neuropsychiatric conditions, such as post-traumatic stress disorder (PTSD), varies greatly among individuals. Fear extinction offers a tractable and translatable behavioral readout of individual differences in learned recovery from trauma. Studies in rodent substrains and subpopulations are providing new insights into neural system dysfunctions associated with impaired fear extinction. Rapid progress is also being made in identifying key molecular circuits, epigenetic mechanisms, and gene variants associated with differences in fear extinction. Here, we discuss how this research is informing understanding of the etiology and pathophysiology of individual differences in risk for trauma-related anxiety disorders, and how future work can help identify novel diagnostic biomarkers and pharmacotherapeutics for these disorders.

Figure I

Extinguishing and non-extinguishing populations, and effects of stress or chronic alcohol in extinguishing populations. (a) A similarly conditioned fear response to a previously neutral stimulus (e.g., tone) repeatedly paired with an inherently aversive stimulus (e.g., electric shock) can be extinguished by repeated presentation of the stimulus in the absence of an aversive outcome in some populations of humans and rodents, but not others. (b) Even in populations that normally extinguish, impairments in either extinction learning and/or retention can be produced by stress or chronic alcohol exposure.

Figure 1

Variation in cortico-amygdala function underlying individual differences in effective extinction versus a bias towards sustained fear. (a) Effective extinction is associated with recruitment of (i) a pathway from the infralimbic cortex (IL), via certain intercalated cell masses (ITC) (and possibly an area known as the capsular IL target zone or intramedullary gray [41,42], not shown), and including the medial central amygdala (CeM) [88]; (ii) connections from a subpopulation of cells in the basal amygdala (BA) [43], some via ITC, to the CeM; and (iii) an inhibitory drive from some cells in the lateral central amygdala (CeL) to CeM [44,89]. (b) Poor extinction and persistent fear is associated with inadequate engagement of extinction circuits and dominance of pro-fear pathways from the lateral amygdala (LA) to BA to CeM [44], as well as reciprocal connections between prelimbic cortex (PL) and BA [16,36]. Note: for simplicity, this model does not include all connections or other brain regions (e.g., hippocampus or thalamus) that likely contribute to individual differences in fear processing and extinction [16,22,23,25]. (c) The rescue of impaired extinction has been tightly coupled to the normalization of many of the corticolimbic abnormalities associated with sustained fear in extinction-impaired populations. An illustrative example is provided by immediate-early gene analysis of neuronal activation in the S1 mouse strain model given the multitarget extinction treatment of dietary zinc restriction [38]. Under basal non-extinction (CS−) conditions, the good-extinguishing B6 (black bars) and poor-extinguishing S1 (red bars) mouse strains do not differ in the number of Zif268-positive cells, in any region, regardless of zinc restriction (ZnR). Following extinction training (CS+), treatment increased activation in previously hypoactive regions (green shading) in the S1 strain that subserve the formation of extinction memories, including the IL, LA, BA, ITC, and CeL, to levels equivalent to baseline activity seen in a good-extinguishing (B6) mouse strain. Conversely, neuronal activity in the previously hyperactive (pink shading), pro-fear regions of the CeM and PL decreased after treatment. This shows how neural abnormalities in extinction-deficient individuals are not permanent and can be effectively reversed by effective drug treatments. Note: for simplicity, neither the insular cortex (hyperactivity in S1 normalized by treatment) nor regions showing no differential activation are shown). Data in bar graphs are redrawn, with permission, from [38].

Figure 2

A strategy for advancing the neurobiological understanding and future treatment of post-traumatic stress disorder (PTSD) by screening for individual differences in fear extinction. The ideal subject pool is a population of individuals with trauma-related anxiety disorders, or fear-conditioned animals, ideally with detailed biographical and/or experimental information on exposure to predisposing environmental risk factors, such as stressful life events and alcohol abuse. Following screening for fear extinction, individuals are selected on the basis of impaired versus intact extinction and compared for aberrant versus effective neural circuit function, respectively. This provides a basis for identifying specific molecules and gene variants underlying these circuit variations, which in turn can lead to pro-extinction therapeutic target development to benefit existing patients, as well as novel biomarkers for the future screening of individuals at elevated risk of trauma-related anxiety disorders.